Findings

A673T is the first variant in APP associated with protection against amyloid pathology and Alzheimer's disease. This variant appears to be restricted primarily to Icelandic and Scandinavian populations.

The A673T variant was first reported in a Caucasian individual who died at the age of 65 with a history of ischemic stroke, but in good cognitive health. Postmortem examination revealed negligible cerebral amyloid in the parenchyma and vessels (Peacock et al., 1993). Two decades later, this rare variant was reported to be more prevalent in non-demented elderly Icelandic individuals than in those with Alzheimer’s disease. Specifically, the A673T variant was five times more common in dementia-free elderly individuals than in people with AD. The A673T variant was also found to protect against age-associated cognitive decline (Jonsson et al., 2012).

The A673T variant was subsequently identified in one out of 515 Finnish individuals over age 85. Although the woman who carried the A673T variant had dementia at the age of 104, her impairment was attributed to hippocampal sclerosis rather than to AD. Overall, her brain contained very little amyloid pathology (CERAD=0), although some vascular amyloid was observed in her meningeal arteries. The minimal amyloid pathology in this A673T carrier, along with her longevity, is regarded as further evidence supporting a protective effect of A673T against amyloid pathology and the development of AD (Kero et al., 2013).

In 2012, the A673T variant was reported in an American woman with a family history of late-onset AD. The proband was originally reported as having late-onset AD, but a later study corrected the classification to unaffected at age 84. Of the 17 family members genotyped, only the proband's mother carried the variant. Like her daughter, she was cognitively healthy into advanced age. Although residing the United States, this family had Scandinavian ancestry (Cruchaga et al., 2012; Wang et al., 2015).

The A673T variant may be restricted primarily to Icelandic and Scandinavian populations. In Icelandic individuals the frequency of the A673T variant was reported as 0.13 percent in AD cases and 0.45 to 0.79 percent in controls. In other control cohorts, frequencies were reported as Norwegian (0.21 percent), Finnish (0.51 percent), and Swedish (0.42 percent) (Jonsson et al., 2012). Recent studies have shown that A673T is extremely rare in Caucasian individuals from the United States and may not play a substantial role in risk of AD in this population. Specifically, it was absent in 1,674 cases with late-onset AD and 2,644 elderly control subjects (Bamne et al., 2014). Another large genotyping study found just three heterozygous Caucasian individuals in North America. Of these, two were cognitively healthy at the ages of 77 and 82, and the third carrier, who was of Russian ancestry, developed AD at the age of 89. Therefore, the study reported a carrier frequency of 0.011 percent in American individuals with AD and 0.018 percent in cognitively normal controls. The same study also identified three heterozygous individuals in a Swedish cohort. All were cognitively healthy at the ages of 55, 59, and 72, respectively. Like Jonsson et al., 2012, this study also found a carrier frequency of 0.42 percent for Swedish controls (Wang et al., 2015).

In contrast to other Nordic populations, the A673T variant may be rare in Denmark. It was present in only 1 of 3,487 Danish individuals (0.014 percent), precluding an assessment of association with longevity or cognitive functioning (Mengel-From et al., 2015).

The A673T variant appears to be extremely rare in Asian populations. It was absent in a screen of 8,721 Asian individuals (Ting et al., 2013), as well as in 1,237 long-lived Chinese individuals (mean age 96.9 years) (Liu et al., 2013).

Neuropathology

This variant is associated with minimal amyloid deposition and is thought to protect against amyloid pathology.

Biological Effect

The A673 residue of APP lies very near the primary β-secretase site, and after cleavage the residue becomes part of the Aβ peptide. Recent in vitro studies suggest that the A673T mutation may reduce amyloid accumulation via effects on both APP and Aβ. Several studies have shown that this variant makes APP a less-favorable substrate for β-secretase, resulting in less Aβ production overall. In addition, the Aβ peptides that are generated are less prone to aggregation.

In addition to lowering Aβ production, the A673T mutation lowers Aβ aggregation. The mutant Aβ, referred to as A2T because it corresponds to position 2 in Aβ, is less aggregation-prone than wild-type Aβ. It is not yet clear whether this reduced aggregation is primarily due to effects on Aβ40, Aβ42, or both (see Benilova et al., 2014; Maloney et al., 2014). A recent study using ion mobility-mass spectrometry showed that Aβ42 with the A2T mutation formed dimers, tetramers, and hexamers, but dodecamer formation was inhibited. In contrast no significant effects on Aβ40 assembly were observed (Zheng et al., 2015)

The A673T variant does not appear to attenuate Aβ toxicity. At a range of concentrations, the neuronal toxicity associated with mutant Aβ40 and Aβ42 was comparable to wild-type Aβ peptides (Maloney et al., 2014). However, there is some evidence that the A673T variant may reduce Aβ-independent neurotoxicity. Neurons expressing APP with the A673T mutation were resistant to TGFβ2-induced cell death (Hashimoto et al., 2014).

Note: The residue A673T in isoform 770 corresponds to A598T in isoform 695, and the mutation is sometimes referred to by the name A598T (e.g., Hashimoto et al., 2014).

Other mutations at this position

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